bims-ecemfi 2026-02-15 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–02–15
nineteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Spatially Heterogeneous Microgel-Annealed PRP-derived Fibrin Hydrogel Promotes Coordinated Vasculogenesis and Angiogenesis After Myocardial Infarction.
Hypoxia restores the acidosis-induced inhibition of cancer cell dissemination.
Dynamic Modulation of the Microenvironment Promotes Functional Maturation of Engineered Tissues.
Glycocalyx micro- and nanodomains in cell-cell and cell-matrix interactions revealed by enhanced click chemistry.
Hydrogel-imposed boundary conditions guide single-lumen neuroepithelial morphogenesis.
Fluorescently Labeled Gradient Hydrogels Reveal Matrix-Dependent Cell Responses to Substrate Stiffness.
Leukocyte-epithelial physical contacts mediate interstitial migration in vivo.
Integrin-Mediated Mechanosensing of Modeled Lymph Node Microenvironment Promotes T Cell Activation via Nuclear Deformation.
Engineering "physically optimized" T cells for increased sampling of complex tumor microenvironments.
Decellularized Extracellular Matrix-Based Tunable 3D Hydrogel: An Alternative Methodology for the Development of a Doxorubicin-Independent 3D Breast Cancer Microphysiological Chemoresistance Model.
Endothelial Cell Autophagy Suppresses Metastasis In Mouse Mammary and Pancreatic Neuroendocrine Tumor Models.
Investigating local negative feedback of Rac activity by mathematical models and cell-motility simulations.
Calcium signalling in glioblastoma networks of different topologies and possible treatments.
Metabolic starvation-induced cell swelling drives solid stress in tumors.
Immune cells adapt to distinct stem cell niches to govern tissue homeostasis.
Cadherin-11 integrates Piezo1 and interleukin-6 signaling to promote fibroblast activation.
Tumoroid model recreates clinically relevant phenotypes of high grade serous ovarian cancer cells, carcinoma associated fibroblasts, and macrophages.
Developmentally inspired synthetic kidney engineering.
An effective method for quantification, visualization, and analysis of 3D cell shape during early embryogenesis.

Acta Biomater. 2026 Feb 10. pii: S1742-7061(26)00085-1. [Epub ahead of print]

Spatially Heterogeneous Microgel-Annealed PRP-derived Fibrin Hydrogel Promotes Coordinated Vasculogenesis and Angiogenesis After Myocardial Infarction.

Yini Huangfu, Yiqun Zhang, Yufeng Zhang, Shuwei Wang, Sheng Ding, Rui Gao, Hang Li, Wenhao Ju, Chuangnian Zhang, Pingsheng Huang, Weiwei Wang, Anjie Dong, Deling Kong, Zujian Feng.

  Blood vessel reconstruction is key for ischemic disease treatment by restoring microvascular perfusion and mitigating pathological tissue stiffening. During neovascularization, the mechanical and biochemical cues presented by the cellular-scale spatial heterogeneity of extracellular matrix (ECM) facilitate the endothelial cells (ECs) spreading and mechanotransduction, thereby driving angiogenesis. Therefore, developing ECM-mimetic proangiogenic biomaterials with compartmentalized spatial heterogeneity is highly desirable but challenging. Here, inspired by the spatially heterogeneous mechanical properties of natural tissues, we designed a series of microgel-annealed hydrogels (GMP) with compartmentalized stress heterogeneity. By integrating microfluidic-synthesized rigid microgels, the soft PRP-derived fibrin matrix was annealed with spatially mechanical domains that direct ECs-guided vascular morphogenesis through mechanotransduction, where rigid microdomains provide anchorage sites for cells adhesion, while soft interstitial matrix permits stalk cells migration and morphogenesis. In vitro, heterogeneous GMP hydrogel augmented ECs mechanotransduction via activating integrin β1-p-FAK-p-MLC signaling pathway and stabilizing VE-CAD/β-cat junctions, promoting 3D vasculogenesis and angiogenesis. In a rat myocardial infarction (MI) model, treatment with the heterogeneous hydrogel enhanced myocardial neovascularization, attenuated ventricular dilation and enhanced cardiac function. These findings not only provide valuable guidance for engineering proangiogenic biomaterials via ECM biomechanical mimicry, but also highlight the promise of spatially heterogeneous hydrogel with engineered mechanical cues essential for de novo blood vessel formation in the treatment of ischemic disease. STATEMENT OF SIGNIFICANCE: This work develops a proangiogenic hydrogel that mimics the spatially heterogeneous mechanical properties of the native extracellular matrix (ECM). By annealing rigid microgels into a soft fibrin matrix, we create a biomaterial with compartmentalized stress domains that guide endothelial cell behavior. This engineered heterogeneity promotes 3D vascular network formation by enhancing key mechanotransduction pathways and stabilizing cell-cell junctions. Significantly, in a rat model of myocardial infarction, the hydrogel enhances neovascularization, attenuates tissue damage, and improves cardiac function. Our findings highlight that recapitulating ECM biomechanical heterogeneity is a transformative strategy for engineering biomaterials to drive functional blood vessel regeneration, offering a promising therapeutic approach for treating ischemic diseases.

Keywords:  extracellular matrix; hydrogel; mechanical heterogeneity; myocardial infarction; proangiogenic biomaterials

DOI:  https://doi.org/10.1016/j.actbio.2026.02.012
Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00048-3. [Epub ahead of print]45(2): 116970

Hypoxia restores the acidosis-induced inhibition of cancer cell dissemination.

Se Jong Lee, Alice Amitrano, Qinling Yuan, Debanik Choudhury, Konstantin Stoletov, Bhawana Agarwal, Avery Tran, Inês Godet, James McCann, Ryan Huizar, Selma A Serra, Pol Picón-Pagès, Norbert Valles, Sangmoo Jeong, Stavroula Sofou, Chen-Ming Fan, John D Lewis, Sean X Sun, Andrew J Ewald, Daniele M Gilkes, Vivek K Bajpai, Miguel A Valverde, Konstantinos Konstantopoulos.

  Acidosis is a hallmark of the tumor microenvironment and has been linked to aggressive cancer behavior, characterized by increased migration, invasion, and metastasis. We herein demonstrate that short-term exposure (24-72 h) to acidic extracellular pH (pHe = 6.4) suppresses cell proliferation, metabolism, dissociation from tumor spheroids, and migration in vitro as well as extravasation in chick embryos and mice. Acidosis acutely inhibits motility by downregulating the activity of sodium-hydrogen exchanger isoform-1 (NHE1), which in turn suppresses phosphatidylinositol 3-kinase (PI3K)/Akt. PI3K/Akt inhibition blocks Yes-associated protein (YAP) translocation to the nucleus, reducing NHE1 and integrin-linked kinase (ILK) expression. The resulting reduction in NHE1-/ILK-dependent migration and ATP production is rescued by hypoxia across cell types. While certain cancer cells can adapt to long-term (>3 weeks) acidosis and acquire an aggressive phenotype, acidosis-induced adaptation is not universal and depends on the cell's ability to restrain reactive oxygen species overproduction via fatty acid oxidation.

Keywords:  Akt; CP: cancer; CP: metabolism; NHE1; YAP; acidosis; cancer; glycolysis; hypoxia; integrin-linked kinase; migration; reactive oxygen species

DOI:  https://doi.org/10.1016/j.celrep.2026.116970
Adv Healthc Mater. 2026 Feb 10. e04573

Dynamic Modulation of the Microenvironment Promotes Functional Maturation of Engineered Tissues.

Eric Silberman, Hadas Oved, Itay Gil, Amgad Marzook, Ester Sapir Baruch, Yahel Shechter, Assaf Shapira, Tal Dvir.

  While extremely complex interactions between cells and extracellular matrix regulate cellular microenvironments in vivo, the pared-down complexity present in engineered tissues is generally insufficient to recapitulate these dynamics in vitro. Here, a biocompatible small molecule that can diffuse into tissues as they mature to dynamically modulate the cellular microenvironment is utilized. This technology can be deployed in multiple doses to repeatedly and controllably adjust the tissue's microenvironment as it matures. It is observed that deploying precisely the same concentration of the small molecule, but at different stages of a tissue's maturation, led to markedly different outcomes. In particular, it is shown that endothelial cells matured in dynamically modulated microenvironments form thicker, more native-like blood vessels than is possible using traditional, non-dynamic culture. Likewise, engineered cardiac tissues generated stronger contractions and demonstrated a more mature electrophysiology when encapsulated in a soft, dynamically modulated hydrogel matrix that allowed for tissue maturation. Finally, the results of differentiating induced pluripotent stem cells to cardiomyocytes within dynamic matrices and show that coordinating the tissue's stiffness with the differentiating cells' developmental stage maximizes their end functionality is presented. The ability to dynamically control the tissue microenvironment during maturation, in a facile and safe manner, represents a significant step toward achieving a more accurate in vitro recapitulation of complex processes vital for tissue engineering.

Keywords:  biofabrication; biomaterials; tissue engineering; tissue maturation

DOI:  https://doi.org/10.1002/adhm.202504573
Nat Commun. 2026 Feb 12.

Glycocalyx micro- and nanodomains in cell-cell and cell-matrix interactions revealed by enhanced click chemistry.

Daan Smits, Johannes A M Damen, Tianfu Li, Floris L van Delft, Bauke Albada, Peter Friedl.

The glycocalyx consists of glycoproteins, glycolipids and extracellular polysaccharides at the cell surface which mediate viscoelastic and electrostatic barrier function. In molecular interactions, the glycocalyx is thought to segregate locally to facilitate receptor-ligand binding, yet high-resolution maps of glycocalyx domains in cell-cell and cell-matrix interactions are lacking. We here apply TMTH-sulfoximine (THS)-based biorthogonal chemistry in live-cell culture and demonstrate enhanced glycocalyx detection, compared to established dibenzocyclooctyne-based labeling. Using superresolution microscopy in cancer cells, we identify micron-scale diminished glycocalyx in cell-cell contacts and depletion in protrusions at the leading and trailing edges and membrane blebs when cells invade 3D fibrillar matrix. At contacts to collagen fibrils, focal integrin clusters segregate ~350 nm outward from the glycocalyx level, forming adhesion sites of low glycocalyx content. Thus, we identify micro- and nanodomains with altered glycocalyx density using THS-based bioorthogonal labeling of live cells, implicating local glycocalyx downregulation in functional cell-cell and cell-matrix interactions.

DOI: https://doi.org/10.1038/s41467-026-69242-1
bioRxiv. 2026 Feb 02. pii: 2026.01.30.702717. [Epub ahead of print]

Hydrogel-imposed boundary conditions guide single-lumen neuroepithelial morphogenesis.

Michelle S Huang, Julien G Roth, Dohui Kim, Kristine P Pashin, Dominic Pizzarella, Tianming M Yang, Yueming Liu, Renato S Navarro, Theo D Palmer, Sarah C Heilshorn.

Three-dimensional (3D) stem cell-based cultures have emerged as promising in vitro model systems for studying human neurodevelopment. Current neural organoid protocols lack well-defined extracellular matrix (ECM) signaling and are limited by the formation of irregular tissue morphologies with multiple organizing centers, in contrast to the single neuroepithelial structure that emerges during embryonic development. This variability limits inter-organoid reproducibility and constrains their utility for modeling early developmental processes. To overcome these limitations, we leverage a materials-based approach to impose dynamic boundary conditions that extrinsically guide the self-organization of human induced pluripotent stem cells (iPSCs). Specifically, we develop a family of hyaluronic acid-elastin-like protein (HELP) hydrogels crosslinked with dynamic covalent bonds that recapitulate key biochemical and biophysical properties of the developing human neural ECM. Within these HELP hydrogels, iPSCs robustly self-organize from a single cell into complex neuroepithelial tissues with a single lumen. By tuning the boundary conditions imposed by the hydrogel, we identify matrix stress relaxation rate and tensional homeostasis as key regulators of single-lumen rosette formation and maintenance. With this hydrogel-enabled system, we identify phenotypic abnormalities in an early neurodevelopmental model of 22q11.2 deletion syndrome. Ultimately, our tunable engineered hydrogel supports the initiation of single-cell derived 3D neuroepithelial tissues, enables investigation into how matrix-imposed boundary conditions guide developmental morphogenesis, and establishes a reproducible platform for disease modeling.

DOI: https://doi.org/10.64898/2026.01.30.702717
Small. 2026 Feb 07. e12198

Fluorescently Labeled Gradient Hydrogels Reveal Matrix-Dependent Cell Responses to Substrate Stiffness.

Shin Wei Chong, Li Liu, Daryan Kempe, Yingqi Zhang, Kourosh Kalantar-Zadeh, Marcela M M Bilek, Lining Arnold Ju, Maté Biro, Daniele Vigolo.

  Microfabricated stiffness gradient hydrogels hold significant value for advancing mechanobiology, tissue engineering, and in vitro tissue models. However, it remains challenging to design these materials given their broad processing parameter space. The continuum of stiffness values also makes it difficult to precisely correlate the local substrate properties and observed biological responses, often relying on cumbersome characterization methods such as atomic force microscopy. To address these bottlenecks, we present a straightforward thermophoresis-based fabrication strategy to pattern stiffness gradients in a fluorescein isothiocyanate-labeled hydrogel network, which displays a polymer concentration-dependent fluorescence readout. This approach enables quantitative assessment of the gradient formation process and contactless stiffness mapping via standard microscopy imaging. Using gelatin methacryloyl and Gellan gum as model systems, it is shown that substrate stiffness and extracellular matrix protein composition work together to affect 3T3-L1 fibroblast cell morphology and migration, with the underlying hydrogel type also affecting the outcome. By offering a simple and reliable approach for characterizing stiffness gradient hydrogels, this work advances the thermophoretic fabrication platform, opening avenues for new biomaterial systems for understanding and controlling the cell-material interplay.

Keywords:  fluorescence; hydrogels; mechanobiology; stiffness gradient; thermophoresis

DOI:  https://doi.org/10.1002/smll.202512198
Res Sq. 2026 Feb 05. pii: rs.3.rs-8594440. [Epub ahead of print]

Leukocyte-epithelial physical contacts mediate interstitial migration in vivo.

Anna Huttenlocher, Jonathan Schrope, Tanner Robertson, Adam Horn, Jack Stevens, Clyde Tinnen, Julie Rindy, Yiran Hou, Emilie Rochon, David Beebe.

Efficient immune cell migration requires physical interactions with surrounding tissues. While tissue matrix mechanics influence leukocyte motility, it is unknown how leukocytes exert pushing and pulling forces to traverse tightly adherent epithelial tissues, which comprise a majority of tissue volume in vivo. Here, we leverage the optical transparency of larval zebrafish to identify how physical interactions with epithelial cells regulate mechanisms of neutrophil force generation to navigate cell-dense tissues. Confining forces from epithelial cells induce a mechanosensitive central actin network, mediated by Cdc42 and WASP, which exerts expansile forces on surrounding cells to dilate a path for migration. In concert, direct cell-to-cell (leukocyte-epithelial) contacts, mediated by integrin ɑE binding to epithelial cadherin, generate tractional forces to enable forward motility. Together, our findings identify how physical interactions with surrounding epithelial cells regulate leukocyte motility through cell-dense tissues in vivo.

DOI: https://doi.org/10.21203/rs.3.rs-8594440/v1
Research (Wash D C). 2026 ;9 1121

Integrin-Mediated Mechanosensing of Modeled Lymph Node Microenvironment Promotes T Cell Activation via Nuclear Deformation.

Jinteng Feng, Guoqing Zhao, Lingzhu Zhao, Luying Geng, Shirong Zhang, Longwen Xu, Mengjie Liu, Guangjian Zhang, Feng Xu, Min Lin, Hui Guo.

Upon tumor metastasis, lymph nodes (LNs) undergo mechanical stiffening, yet how this change influences T cell activation within the microenvironment remains incompletely understood. In particular, the dynamic mechanical forces during activation are transduced by cell-extracellular matrix (ECM) interactions, while cell-cell interactions persist. Here, we established a novel T cell culture platform using hydrogels with tunable stiffness and decoupled presentation of RGD peptide and anti-CD3 monoclonal antibody, separately mimicking ECM-T cell and T cell-antigen-presenting cell interactions. This platform closely mimics the LN microenvironment during T cell activation. By integrating experiments with mathematical modeling, we revealed that T cells sensed mechanical changes in the microenvironment requiring RGD/integrin ligation, while stiff matrix up-regulated F-actin aggregation instead of myosin contraction, deforming the nucleus and promoting yes-associated protein nucleus translocation, resulting in interleukin-2 expression and T cell activation. Our findings shed light on the mechanobiological mechanism underlying the potential benefits of immunotherapy in patients with LN metastases and provide an optimized mechanical platform for studying T cell activation and expansion in vitro.

DOI: https://doi.org/10.34133/research.1121
bioRxiv. 2026 Feb 01. pii: 2026.01.28.702394. [Epub ahead of print]

Engineering "physically optimized" T cells for increased sampling of complex tumor microenvironments.

Hongrong Zhang, Zhongming Chen, Guhan Qian, Christopher D Zahm, Roberto Alonso-Matilla, Salena Fischer, Ingunn M Stromnes, Beau R Webber, Kevin W Eliceiri, David J Odde, Branden S Moriarity, Paolo P Provenzano.

Pancreatic ductal adenocarcinoma (PDA) remains highly lethal, in part, because its dense fibroinflammatory stroma restricts therapy distribution, including adoptive T cell immunotherapies where direct interactions between T and carcinoma cells are essential for effective therapy. While T cell function must be maintained once effector-target engagement occurs, without inducing co-localization subsequent cytotoxic function steps cannot be undertaken. We therefore developed a strategy to "physically optimize" T cells to more effectively sample complex tumor volumes. Informed by pharmacologic perturbations and mathematical modeling we shifted T cell phenotype through expression of constitutively activated RhoA to increase cortical contractility, activation, migration, and sampling in PDA, while showing decreases in exhaustion markers. In CAR T cells this results in more efficient targeting through decreased sampling time and increased engagement with carcinoma cells, consistent with modeling predictions. This significantly increases T cell infiltration and distribution in PDA, resulting in improved tumor control in vivo, suggesting that this is an effective strategy to overcome stromal constraints, improve tumor engagement, and enhance the therapeutic performance of engineered T cell therapies in solid tumors.

DOI: https://doi.org/10.64898/2026.01.28.702394
ACS Appl Bio Mater. 2026 Feb 12.

Decellularized Extracellular Matrix-Based Tunable 3D Hydrogel: An Alternative Methodology for the Development of a Doxorubicin-Independent 3D Breast Cancer Microphysiological Chemoresistance Model.

Mohammed Shabib, Mamta Kumari, Ujjwal Gupta, Sangita Dan, Chandan Mondal, Santanu Kaity, Subhadeep Roy.

  Breast cancer is the most prevalent malignancy among women and the second leading cause of cancer-related mortality worldwide, with 2.26 million cases and 685,000 deaths in 2020. Its complex nature complicates treatment, and emerging evidence shows that extracellular matrix (ECM) biomechanics, particularly stiffness, dynamically change in response to physiological and pathological cues. These alterations influence malignant cell morphology and promote chemoresistance by regulating tumor growth, invasion, and metastasis. Clinically, breast tumor ECM stiffness (2-100 kPa) is markedly higher than that of healthy breast tissue (0.1-1 kPa). Developing 3D models that accurately recapitulate breast cancer ECM stiffness remains challenging, as current systems lack physiologically relevant crosslinking and rheology. Increasing evidence suggests that ECM stiffness alone can drive chemoresistance; thus, precise in vitro replication of tumor matrix biomechanics may induce drug-resistant phenotypes through mechanical cues. A key unresolved question is how matrix rigidity mechanistically regulates therapeutic resistance? Is it possible to create a chemoresistance model without any drug exposure? In this work, Pork Achilles tendon was decellularized using surfactants (SDS-Triton X-100) and enzymes (Collagenase-Dispase and Trypsin-EDTA), preserving ECM structure and biomechanics, and engineered into a customizable photo-cross-linked 3D hydrogel to study the effects of matrix crosslinking and rheology on in vitro chemoresistance. H&E staining and SEM were used to characterize the decellularized tissue. Further, we lyophilized and cryo-milled the decellularized tissue into a fine powder to fabricate a photo-cross-linked 3D hydrogel with tunable matrix crosslinking and rheology. Drug resistance was evaluated by culturing MDA-MB-231 cells encapsulated in 3D hydrogels with variable matrix crosslinking and rheology, and assessing the CD44+/CD24- cancer stem cell-associated phenotype linked to aggressiveness and therapy resistance.

Keywords:  3D hydrogel; Breast cancer; Chemoresistance; Decellularization; Extracellular matrix; Variable matrix cross-linking and rheology

DOI:  https://doi.org/10.1021/acsabm.5c02380
bioRxiv. 2026 Jan 29. pii: 2026.01.28.702341. [Epub ahead of print]

Endothelial Cell Autophagy Suppresses Metastasis In Mouse Mammary and Pancreatic Neuroendocrine Tumor Models.

Nancy León-Rivera, Brayden Chin, Ashley Quintana, Sofia Bustamante-Eguíguren, Anthony Gacasan, Monica Nanni, Jayanta Debnath, Teresa Monkkonen.

Autophagy, a key lysosomal degradation pathway regulating metabolic adaptation in cancer, plays fundamental roles in both the tumor and host stromal compartments during cancer progression. An important unanswered question is whether and how autophagy in specific host stromal elements, such as endothelial cells, influences metastasis. Here, we scrutinize how the genetic loss of autophagy in endothelial cells impacts primary tumor progression and metastasis in the Polyoma Middle T ( PyMT ) model of luminal B breast cancer. In both autochthonous and orthotopic mammary transplant models, PyMT primary tumor growth is significantly delayed upon endothelial cell Atg12 or Atg5 genetic deletion ( Atg12 or 5 ECKO), which correlates with increased tumor cell apoptosis and HIF1α activation. In contrast, PyMT -bearing Atg12 ECKO mice exhibit increased metastasis, as well as higher rates of primary tumor and lung metastatic recurrence following surgical resection of PyMT primary tumors. Experimental metastasis assays further corroborate that loss of endothelial cell autophagy in Atg12 ECKO host animals promotes PyMT metastatic colonization and outgrowth, resulting in increased lung metastases compared to controls. Similarly, in the Rat Insulin Promoter T antigen pancreatic neuroendocrine tumor (RT2-PNET) model, endothelial cell deletion of Atg12 promotes liver micro-metastases. Taken together, these results from distinct preclinical cancer models reveal that endothelial cell autophagy suppresses metastatic seeding and progression and broach that autophagy inhibition in host endothelial cells may adversely influence the efficacy of systemic autophagy-lysosomal pathway inhibition in the clinical oncology setting.

DOI: https://doi.org/10.64898/2026.01.28.702341
iScience. 2026 Feb 20. 29(2): 114641

Investigating local negative feedback of Rac activity by mathematical models and cell-motility simulations.

Jupiter Algorta, Jason P Town, Orion D Weiner, Leah Edelstein-Keshet.

  How do cells maintain robust, yet flexible polarization for directed motion? Recent optogenetic experiments by Town and Weiner on neutrophil-like HL-60 cells strongly point to the essential role of a Rac-inhibitor (downstream of the small GTPase Rac) in shaping requisite negative feedback that allows cells to respond to rapidly changing directional cues. Here we adapt a previous mathematical model for cell polarity to model interactions of Rac, its putative inhibitor, and upstream PIP3 (a product of the optogenetically stimulated PI3K). We fit parameters in our partial differential equation (PDE) model to temporal and spatial experimental data. Cell shapes, motility, and stimulus responses are modeled in 2D simulations, with PDEs solved along the cell edge. We show that the Rac-inhibitor-PIP3 circuit accounts for the optogenetic data (including exotic cell trajectories), that it is the minimal circuit to do so, and that it improves gradient sensing under noisy or dynamic conditions.

Keywords:  Cell biology; Mathematical biosciences

DOI:  https://doi.org/10.1016/j.isci.2026.114641
Math Biosci. 2026 Feb 05. pii: S0025-5564(26)00028-3. [Epub ahead of print]394 109638

Calcium signalling in glioblastoma networks of different topologies and possible treatments.

Alexandra Shyntar, Thomas Hillen.

  Glioblastoma cells form connected cell networks, utilizing tumor microtubes (TMs) to transmit calcium between cells. A new cell type called "periodic cell" is integral in sustaining calcium signalling in a glioblastoma network. Periodic cells are rare, can sustain consistent intracellular calcium transients, are likely to have KCa3.1 pumps, and have on average more TMs than other glioma cells. Here, we adapt an ordinary differential equation model for intracellular as well as intercellular calcium signalling and apply it to a large glioma cell network. Using the model, three main hypotheses were tested for the mechanism behind the sustained calcium oscillations in periodic cells: 1. a fixed and elevated IP3 concentration, 2. added benefit from influx of calcium due to KCa3.1 pumps, or 3. oscillation in calcium influx into the cell through the plasma membrane. All three hypotheses yield similar calcium oscillation patterns resembling the trends seen in the data of Hausmann et al. 2023. In vivo, glioma networks were shown to have small-world and scale-free network properties. We apply our model to small-world, scale-free and random networks and test how communication is inhibited through removal of cells, removal of tumor microtubes, and inhibition of KCa3.1 pumps. All three network types were more vulnerable to random cell damage than to random TM damage. We find that inhibition of KCa3.1 pumps can have a significant impact on the inhibition of network communication, however, to fully degrade the calcium signalling network, all periodic cells must be eradicated confirming experimental observations.

Keywords:  Calcium signalling; Glioma network; Mathematical oncology; Periodic cells; Random network; Scale-free network; Small-world network

DOI:  https://doi.org/10.1016/j.mbs.2026.109638
bioRxiv. 2026 Feb 08. pii: 2026.02.05.704098. [Epub ahead of print]

Metabolic starvation-induced cell swelling drives solid stress in tumors.

Mohammad Dehghany, Vivek Sharma, Akash Samuel Annie-Mathew, Andrei Zakharov, Tom Hu, Guilherme Pedreira de Freitas Nader, Vivek Shenoy.

Solid stress shapes tumor growth, invasion, and therapeutic response, yet its physical origin and clinical relevance remain unclear. Here, we develop a mechano-electro-osmotic model integrating metabolic gradients, ion transport, and cellular mechanics to explain residual solid stress emergence in tumor spheroids, common models of solid tumors. We show that solid stress arises predominantly from osmotic cell swelling driven by metabolic deprivation and ion accumulation, rather than proliferation. This mechanism generates a characteristic stress architecture: isotropic compression in the hypoxic core balanced by peripheral tangential tension, causing pronounced cell and nuclear deformation. The resulting nuclear strain provides a mechanical basis for DNA damage and genomic instability implicated in disease progression and treatment resistance. We validate these predictions in breast cancer using MDA-MB-231 spheroids and patient-derived ductal carcinoma in situ lesions, and corroborate them across published spheroid models and in vivo and ex vivo tumors spanning additional cancer types. Our findings link tumor metabolism to clinically relevant mechanical stresses, suggesting opportunities to target osmotic and metabolic pathways to mitigate solid stress and improve therapeutic outcomes.

DOI: https://doi.org/10.64898/2026.02.05.704098
bioRxiv. 2026 Jan 31. pii: 2026.01.28.701831. [Epub ahead of print]

Immune cells adapt to distinct stem cell niches to govern tissue homeostasis.

S Martina Parigi, Sairaj M Sajjath, Charlotte J Bell, Shaopeng Yuan, Vitoria M Olyntho, Alain R Bonny, Sandra Nakandakari-Higa, Sergio A Lira, Daniel Mucida, Gabriel D Victora, Elaine Fuchs.

In adult tissues, epithelial stem cells exist within distinct residences, each endowing them with exclusive instructions for regenerative fitness under homeostasis and stress. Key components of these 'niches' are immune cells, which classically protect the host against external and internal threats. Whether and how stem cell:immune cell crosstalk contributes to normal tissue biology remains less clear. Here, we discover functional adaptation of resident lymphocytes within two distinct skin stem cell niches and show that through this communication, each niche adjusts to meet diverse tissue demands. In the upper hair follicle, where microbial load is high, T cells express lymphotoxin-β and stimulate adjacent receptor-positive epithelial stem cells to form an immune-competent niche that controls microbial expansion. By contrast, in the epidermis, these T cells produce amphiregulin to maintain continuous stem cell reconstitution of the skin's barrier. Concomitantly, they express the immune checkpoint protein 'LAG-3', which autorestricts lymphocyte numbers, and hence amphiregulin levels, thereby preventing over-proliferative responses. Finally, when epidermal T cells are absent, dermal lymphocytes restore the imbalance by colonizing and adapting to their new niche. Our findings unveil functional specialization and homeostatic resilience of immune-stem cell niches, each tailored to suit the demands of distinct tissue microenvironments.

DOI: https://doi.org/10.64898/2026.01.28.701831
Biomater Sci. 2026 Feb 09.

Cadherin-11 integrates Piezo1 and interleukin-6 signaling to promote fibroblast activation.

Leilani R Astrab, Steven R Caliari.

Persistent fibroblast activation drives tissue fibrosis, yet how mechanical and inflammatory cues are integrated to promote this aberrant behavior remains unclear. Using a hyaluronic acid (HA)-based hydrogel platform to model normal and fibrotic lung mechanics, we examine the roles of Piezo1 and cadherin-11 (CDH11), both implicated in M2 macrophage-fibroblast crosstalk during pulmonary fibrosis progression, in interleukin (IL)-6-mediated fibroblast activation. While both Piezo1 and CDH11 expression increase in activated fibroblasts, blocking IL-6 signaling decreases CDH11, but not Piezo1, expression. Instead, Piezo1 activity promotes nuclear accumulation of the calcium-dependent transcription factor NFAT1. While Piezo1 inhibition moderately reduces CDH11 expression, it does not prevent fibroblast activation as measured by spreading and type I collagen expression, whereas CDH11 knockout suppresses fibroblast activation metrics, reduces Piezo1 expression, and decreases IL-6 secretion in both fibroblast only and fibroblast-M2 macrophage co-cultures. Furthermore, CDH11 levels increase in parallel with progressive fibroblast activation, highlighting its role in promoting this pro-fibrotic phenotype. Together, these findings underscore a previously unrecognized signaling axis in which CDH11 serves as a key mediator of sustained fibroblast activation, coordinating mechanical and inflammatory cues, and highlight CDH11 as a potential therapeutic target in pulmonary fibrosis.

DOI: https://doi.org/10.1039/d5bm01456e
Acta Biomater. 2026 Feb 06. pii: S1742-7061(26)00078-4. [Epub ahead of print]

Tumoroid model recreates clinically relevant phenotypes of high grade serous ovarian cancer cells, carcinoma associated fibroblasts, and macrophages.

Kathleen M Burkhard, Ayush Semwal, Benjamin K Johnson, Kristina C Chu, Riley J Kranick, Mihika Rayan, Analisa DiFeo, Hui Shen, Geeta Mehta.

  Ovarian cancer, the gynecological malignancy with the lowest survival rate, is significantly influenced by the tumor microenvironment. The mesenchymal subtype of high-grade serous carcinoma (HGSC) shows poor outcomes due to high stromal and low immune response. Single-cell RNA sequencing (scRNA-seq) of HGSC metastatic ascites has identified carcinoma-associated fibroblasts (CAFs), macrophages, and carcinoma-associated mesenchymal stem cells (CA-MSCs) as crucial drivers of immune exclusion, chemotherapy resistance, metastasis, and stem-like cell propagation. To explore this complex signaling, we developed heterogeneous tri-component tumoroids, incorporating HGSC cells (OVCAR3, OVCAR4, OVCAR8), primary MSCs, and U937-derived M2-like macrophages (M2) in defined ratios, each labeled with a fluorescent protein for distinct analysis. Upon a 48-hour treatment with carboplatin and/or paclitaxel, HGSC cells in tri-component tumoroids exhibited higher chemoresistance than HGSC-only tumoroids. Flow cytometry revealed significant increases in cancer stem-like cell (CSC) markers CD44 and CD90 in the tri-component tumoroids. Conditioned medium from the tri-component tumoroids significantly enhanced HGSC cell migration. Invasion assays further demonstrated that tri-component tumoroids penetrated monolayer of mCherry-labeled LP-9 mesothelial cells more effectively than HGSC-only tumoroid. Additionally, scRNA-seq of tri-component tumoroids identified a unique cancer cell cluster enriched in epithelial-mesenchymal transition (EMT) and matrisome signatures, featuring a 14-gene signature linked to poor survival. MSCs in these tri-component tumoroids displayed a myofibroblastic-CAF signature, while macrophages indicated an ECM-associated and immunosuppressive phenotype. In conclusion, our 3D heterogenous tri-component tumoroids replicate key HGSC phenotypes, such as chemoresistance, CSC enrichment, migration, invasion, and EMT. This platform is invaluable for studying HGSC microenvironment interactions and preclinical testing of targeted therapies. STATEMENT OF SIGNIFICANCE: The cellular composition of the ovarian tumor microenvironment has a profound effect on patients' clinical outcomes, yet effective therapies that target its cellular components remain underexplored. In this study, we introduce a highly tunable 3D in vitro tumoroid model for ovarian cancer that integrates stromal cells, such as mesenchymal stem cells (MSCs) and macrophages, with cancer cells to more accurately recapitulate the complex cell-cell interactions of these heterogeneous tumors. This model facilitates detailed investigation of intercellular signaling pathways, enabling the identification of previously unexplored therapeutic targets. Generated using a 384-well hanging drop array, these tri-component tumoroids are compatible with high-throughput drug screening. This versatile platform can be adapted for a range of stromal cell types, making it broadly applicable for studying ovarian as well as other solid tumor microenvironments.

Keywords:  Alternately activated macrophages; Carcinoma-associated mesenchymal stem cells (MSC) (CA-MSC); High grade serous ovarian cancer; Molecular subtyping; Organoids; Spheroids; Tri-component tumoroids; Tumor associated macrophages (TAM); Tumor microenvironment; scRNA-seq

DOI:  https://doi.org/10.1016/j.actbio.2026.02.005
Nat Biotechnol. 2026 Feb 10.

Developmentally inspired synthetic kidney engineering.

Emma Warrner, Aria Zheyuan Huang, Alex J Hughes.

Developmentally inspired kidney tissues derived from stem cells hold promise for future renal replacement tissue, but clinical translation is limited by variability in outcomes, absence of cell types, lack of functional maturity and implausible scalability. Overcoming these may benefit from tissue engineering strategies that leverage processes for tissue construction that the embryonic kidney uses to achieve its diverse and parallelized functions. We present a 'developmental engineering' strategy in which spatial and temporal cues inspired by in vivo development guide multiscale structure formation in vitro. We highlight emerging tools in synthetic biology, spatial patterning and control over tissue microenvironments that can set initial and boundary conditions to instigate and guide the development of a desired 'motif'. We then present a vision for scalable developmental engineering by guiding and daisy-chaining tissue motifs, bridging discontinuities in self-organization via direct assembly. Although we articulate a blueprint for developmental engineering of translationally viable renal replacement tissues, the strategy is also applicable to other solid organs.

DOI: https://doi.org/10.1038/s41587-026-03011-9
Quant Biol. 2025 Mar;13(1): e83

An effective method for quantification, visualization, and analysis of 3D cell shape during early embryogenesis.

Zelin Li, Zhaoke Huang, Jianfeng Cao, Guoye Guan, Zhongying Zhao, Hong Yan.

  Embryogenesis is the most basic process in developmental biology. Effectively and simply quantifying cell shape is challenging for the complex and dynamic 3D embryonic cells. Traditional descriptors such as volume, surface area, and mean curvature often fall short, providing only a global view and lacking in local detail and reconstruction capability. Addressing this, we introduce an effective integrated method, 3D Cell Shape Quantification (3DCSQ), for transforming digitized 3D cell shapes into analytical feature vectors, named eigengrid (proposed grid descriptor like eigen value), eigenharmonic, and eigenspectrum. We uniquely combine spherical grids, spherical harmonics, and principal component analysis for cell shape quantification. We demonstrate 3DCSQ's effectiveness in recognizing cellular morphological phenotypes and clustering cells. Applied to Caenorhabditis elegans embryos of 29 living embryos from 4- to 350-cell stages, 3DCSQ identifies and quantifies biologically reproducible cellular patterns including distinct skin cell deformations. We also provide automatically cell shape lineaging analysis program. This method not only systematizes cell shape description and evaluation but also monitors cell differentiation through shape changes, presenting an advancement in biological imaging and analysis.

Keywords:  Caenorhabditis elegans (C. elegans); cell shape quantification; eigen features (eigengrid, eigenharmonic & eigenspectrum); lineage analysis; morphological reproducibility; spherical harmonics (SPHARM)

DOI:  https://doi.org/10.1002/qub2.83